Chapter 1Introduction

Defining OAB

Overactive bladder syndrome, referred to as OAB in this report, is formally defined as:

• urgency, which is the complaint of sudden need to void;
• with or without urge incontinence, involuntary loss of urine with urgency symptoms;
• usually with frequency, which is the individual’s perception that she voids too often during the day, and is often defined as more than eight voids during waking hours;
• usually with nocturia, which is awakening from sleep to empty the bladder.

This operational definition was formally standardized as part of a consensus process of experts, in 2002 by the International Continence Society (ICS) as part of an effort to promote healthcare professionals’ and researchers’ use of common terminology in the care and study of women with OAB. Components of the syndrome have had varied, and at times conflicting, nomenclature that include detrusor (bladder muscle) instability; detrusor dysfunction; detrusor dysynergia; detrusor overactivity, and irritable bladder. In each case, these terms shared a causal model that hypothesizes that mistimed or poorly regulated bladder contractions create the sensation of sudden need to void with or without leakage. However clinical study of bladder muscle function using urodynamic testing to measure characteristics like bladder capacity, pattern and timing of bladder contractions, and bladder volume at which women first experienced the urge to void, did not reveal uniform test results among women who had identical complaints. Lacking a reliable biologic marker to define and describe the severity of the condition with objective tests of the bladder itself, clinicians, researchers, pharmaceutical companies, and others came to conceptualize the symptoms of OAB, which often appeared in combination, as a syndrome.

Syndromes are medical conditions defined by the symptoms, which are the sensations (urgency), changes (frequency), or events (incontinence episodes) experienced by the individual. A syndrome is not defined by a known biologic cause. The pathophysiology of OAB is incompletely characterized and the syndrome is a diagnosis of exclusion reached when other causes of the symptoms, like urinary tract infection, urethral inflammation, or neurologic causes of incontinence are ruled out as the cause. OAB symptoms may be life long, relapsing and remitting; or may completely resolve; which manifestations of the syndrome a woman has may also vary over time. However followup studies that track women who have OAB find that on average it is a chronic condition that women experience for a year or more at a time, and may have into the indefinite future.

Little is known about causes and most physiology and clinical research aimed at understanding etiology is now focused at the descriptive and hypothesis development and testing phase of investigation. The most promising theories postulate abnormalities in control of bladder function resulting from aberrations in neurologic signals from the bladder (sensation) and in central and peripheral nervous system regulation.

OAB and Awareness of the General Public

Prior to the mid-1990s research and clinical care focused on describing and managing frank incontinence. The term “overactive bladder” was introduced into the lexicon in the mid-1990s by Pharmacia (acquired by Pfizer in 2002) to describe the frequent urge to urinate as part of its advanced marketing campaign of Detrol (tolterodine). The company framed this as an opportunity to “destigmatize” a range of symptoms encompassing urgency, frequent voiding, and urge incontinence, so that patients would not be afraid to speak with their doctors about the problem.¹⁸¹ The construct – and subsequent marketing success – of OAB medications revolved around encouraging women to reflect on how their symptoms influenced their quality of life and the degree to which the symptoms caused inconvenience, emotional distress, withdrawal from activities, or sexual problems.

As a result, a broader spectrum of women, extending beyond those with incontinence, became candidates for treatment. This included those who were inconvenienced by or worried about frequent urination or who engaged in what has been referred to as “defensive voiding”, emptying the bladder in an attempt to extend the interval between symptoms or to reduce the amount of urine that leaks with incontinence, and “toilet mapping,” being aware of where bathrooms are and canvassing new locations to be sure the options are known. The group of those encouraged to consider treatment also came to include women who perceive they urinate more than “normal” and women whose jobs or lifestyles do not accommodate frequent, strong urges to urinate. Early advertisements featured school crossing guards and jurors who could not readily take a break. Momentum toward a very broad definition in marketing was a factor in the updated consensus definition of OAB by the ICS in 2002, so that the biomedical community would have an opportunity to formally standardize the definition with specificity.

Marketing of drug and the drug indication to physicians occurred through the usual channels, such as paid educational trips, speaking engagements, outsourcing drug studies, etc.^{182, 183} Nearly simultaneously, as a result of less restrictive rules about direct to consumer marketing, women were reached directly through the power of television and print media in new ways.¹⁸⁴ Use of “buzz drivers,” or people paid to promote the drug during news broadcasts or celebrity interviews came into play as new marketing techniques.¹⁸⁵ By 2006, the first drug to specifically target the broader definition of OAB hit the blockbuster mark of $1 billion in sales for the year.¹⁸⁶ Two drugs, tolterodine tartrate and oxybutynin, were the only drugs approved in the United States specifically for OAB until 2004 when trospium, darifenacin, and solifenacin were introduced.¹⁸⁷ Fesoterodine, a metabolite of tolterodine was approved in October 2008. Oxybutynin is now available in a transdermal formulation. Thus over roughly a decade – a very short time window in clinical medicine – both the condition of OAB and pharmaceutical treatments for OAB became part of the consciousness of the public and the general medical community alike.

Scope of the Report

Evidence reviews of therapeutics seek to identify and systematically summarize objective information about the evidence related to:

• Effectiveness of specific, well-defined treatments
• Relative benefit of one treatment over another
• Common side effects and serious risks of a treatment
• Whether individual characteristics help predict who will benefit or be harmed
• Degree to which individuals find the treatment acceptable or satisfactory
• Costs of care or risk-benefit assessments

Key Questions

For this review, we operationally defined OAB as “idiopathic urinary urgency and frequency with or without associated incontinence in adult females, not related to neurogenic conditions or as a result of (incontinence) surgery.” This review is restricted to OAB, rather than exclusively mixed incontinence, stress incontinence, painful bladder syndrome, and other lower urinary tract symptoms (LUTS).

We have synthesized evidence in the published literature to address these key questions:

• KQ1. What is the prevalence and incidence of overactive bladder as estimated in representative populations?
• KQ2. Among women with overactive bladder, what are the short and long-term outcomes of the following treatments, or combinations of treatment approaches:
  1. Pharmacologic treatments
  2. Surgical and procedural treatments
  3. Behavioral and physical therapy treatments
  4. Complementary and alternative medicine treatments
• KQ3. Where direct comparisons have been made between or among treatment modalities of interest, which modalities achieve superior outcomes with respect to benefits, short and long-term risks, and quality of life?
• KQ4. Are the short and long term outcomes of these treatment approaches modified by clinical presentation, physical exam findings, urodynamic findings, menopausal status, age, or other factors?
• KQ5. What are the costs associated with these treatment approaches?

Analytic Framework for the Treatment of OAB Women

The analytic framework in Figure 1 summarizes the conceptual model used to guide this systematic review by focusing the key questions on critical health care-related pathways and decision points. We recognize a number of other factors like provider prescribing preferences and types of testing performed for a patient presenting with symptoms are part of this pathway. However little literature was available to inform other nodes in the process of care.

Figure 1

Analytic framework for the treatment of OAB in women.

Organization of this Evidence Report

Chapter 2 describes our methods including our search strategy, inclusion and exclusion criteria, approach to review of abstracts, to review of full publications, and for extraction of data into evidence tables, compiling evidence, and when possible conducting meta-analysis. We also describe the approach to grading of the quality of the literature and to describing the strength of the literature.

Chapter 3 presents the results of the evidence report by key question, synthesizing the findings across treatment type. We report the number and type of studies identified and we differentiate between total numbers of publications and unique studies to bring into focus the number of duplicate publications in this literature in which multiple publications are derived from the same study population. We emphasize the effect of treatment on the core symptom complex of OAB. Chapter 4 discusses the results in Chapter 3 and enlarges on methodologic considerations relevant to each key question. We also outline the current state of the literature and challenges for future research on OAB.

We have prioritized reporting on clinically relevant commonalities for United States care settings, being aware of the fact that primary care generalists and specialists alike are called upon to evaluate and treat OAB patients. We placed greatest value on the studies, and the content within studies, that is most likely to be applicable to help guide patient care, such as treatment selection, as well as inform anticipatory guidance about likely magnitude of treatment effects and risk of both nuisance side effects and serious harms.

Technical Expert Panel (TEP)

We identified technical experts on the topic of OAB in the fields of urology, urogynecology, gynecology, primary care, nursing, and patient advocacy to provide assistance during the project. The TEP (see Appendix E) was expected to contribute to AHRQ’s broader goals of (1) creating and maintaining science partnerships as well as public-private partnerships and (2) meeting the needs of an array of potential customers and users of its products. Thus, the TEP was both an additional resource and a sounding board during the project. The TEP included twelve members serving as technical or clinical experts, including an AUA representative. To ensure robust, scientifically relevant work, we called on the TEP to provide reactions to work in progress and advice on substantive issues or possibly overlooked areas of research. TEP members participated in conference calls and discussions through e-mail to:

• Refine the analytic framework and key questions at the beginning of the project;
• Discuss the preliminary assessment of the literature, including inclusion/exclusion criteria;
• Provide input on the information and categories included in evidence tables;
• Develop a hierarchy of participant characteristics and outcomes to systematically assess;
• Advise about the clinical availability, use, and most common doses for therapeutics.

Because of their extensive knowledge of the literature, including numerous articles authored by TEP members themselves, and their active involvement in professional societies and as practitioners in the field, we also asked TEP members to participate in the external peer review of the draft report.